Cell envelope maintenance by PhoP is essential for <i>Mycobacterium tuberculosis</i> methylglyoxal resistance

During <i>Mycobacterium tuberculosis</i> infections bacteria are engulfed by macrophages, a main line of defense against invading pathogens. Upon activation, macrophages increase glycolysis, producing the antibacterial aldehyde methylglyoxal. To test whether bacterial methylglyoxal resistance is required for robust infections, we sought to identify <i>M. tuberculosis</i> defense mechanisms against methylglyoxal. We identified <i>phoP</i> mutants were among the most highly sensitive strains to methylglyoxal in vitro. <i>phoP</i> mutants are highly attenuated in mice but a <i>phoP</i> mutant was even more attenuated in mice that accumulate methylglyoxal. We further found <i>phoP</i> bacilli were more permeable to methylglyoxal and accumulated glycated proteins. Suppressor mutations in the fatty acid β-oxidation genes <i>fadE25</i> or <i>fixB</i> restored impermeability and resistance to methylglyoxal to a <i>phoP</i> mutant. Together, our data show that an important role for PhoP is to provide <i>M. tuberculosis</i> resistance to methylglyoxal toxicity in vivo by regulating cell envelope integrity.